Ureapoietic organ replacement

ABSTRACT

The invention relates to a bionic organ replacement which has a structure consisting of three groups of textile hollow microfibers. The hollow microfibers of each group run into in a liquid conductor which is central respectively. The hollow microfibers of the first group ( 1 ) are made from a proton-conducting material and have perforations ( 2 ) for draining bile into the area inside the fibers ( 1 ). One of the surfaces in essentially every hollow microfiber ( 1 ) of the first group ( 1 ) is hydrophilic and lipophilic whilst the other surface is hydrophobic and lipophobic. Cell cultures can be grown on the outer surfaces of all of the hollow microfibers.

The invention relates to a bionic organ replacement, i.e. an “artificialliver” for intracorporeal as well as extracoporeal application.

It is general knowledge that different metabolic processes occur in thehuman liver. The digestive products are stored and processed in thehepatocytes. In addition, essential importance is attributable to theliver as a detoxification organ.

The different structures of the hepatocytes, the cytoplasm, the fine andrough endoplasmic reticulum, lycosomes, peroxisomes and the Golgicomplex with mitochondria, each carrying out their respective differentfunctions. As an example mention is made of the generation of urea, thediamide of carbon dioxide in the mitochondrial matrix of thehepatocytes. The formation of bile, i.e. bile salts and bile pigments isalso part of the functions of the liver. The bile fluid which isseparated by the hepatocytes as secretion is received by theinterlobular gall capillaries and transmitted to the interhepatic gallducts.

It is the object of the present invention to provide an organreplacement which is capable, in case of existing organ insufficiency ororgan failure, to assume said functions, at least in part, and which issuitable for intracorporeal as well as extracorporeal application.

Said object is solved according to the invention by a ureapotetic organreplacement in accordance with claim 1.

The bionic organ replacement has a structure consisting of three groupsof hollow textile micro fibers, whereby the hollow micro fibers of eachgroup issue into at least one respectively central liquid conductors,with the hollow micro fibers of the first group being made ofproton-conducting material and having perforations for drainage of bilefluid into the interior of the fibers and one of the surfaces ofessentially every hollow microfiber of the first group being hydrophilicand lipophilic, whereas the other of the surfaces is hydrophobic andlipophobic, and whereby cell cultures can be grown on the outer surfaceof all of the hollow micro fibers.

The invention-specific organ replacement is designed in such manner thatif hepatocytes are cultured on the surfaces of the hollow micro fibers,said organ replacement is capable of essentially fulfilling allfunctions of the liver, both intracorporeal as well as extracorporeal.The hollow micro fibers of the structure have textile properties, i.e.they are extremely fine and flexible. They form the capillary vessels ofthe artificial liver.

The human liver is constructed of approximately 1 to 1.5 million ofliver lobules (lobuli hepati), which have a height of approximately 2 mmand a diameter of approximately 1 to 3 mm and consist of liver cells(hepatocytes) which are arranged approximately polyhedrally. The bilewhich is formed in the liver lobules is drained as secretion via theinterlobular gall capillaries and the small gall ducts into the gallbladder (vesica fellea) or via the gall duct (ductus chlodeochus)directly into the small intestine. The interlobular gall capillariesgenerally have a diameter from 0.1 to 1.5 μm but can, however, in caseof obstruction of the bile flow expand to approximately 15 to 20 μm.

The functions of the interlobular gall capillaries in the organreplacement according to the invention are carried out by the hollowmicro fibers of the first group. They must be made of a material, thesame as the natural gall capillaries, which is proton-conductive.Apatit, for example, as well as some polymers, specificallypolytetrafluorethylene, have proven themselves suitable for saidpurpose. In order to provide the larges possible surface for culturingthe cells, preference is given to spongiform hollow micro fibers. Inaddition, the fibers must be structured in such manner that they willselectively pass the involved metabolites, in other words, they aresemi-permeable.

Another requirement consists in that one of the surfaces of each hollowmicro fiber of the first group, preferably the inner surface, islipophobic and hydrophobic and the other surface, preferably the outersurface, lipophilic and hydrophilic. In this fashion decomposition ofthe cells can be prevented by the bile formed in the hepatocytes. Thesurfaces of the hollow micro fibers can, for example, be renderedlipophobic or hydrophobic, in other words they can be “sealed” by acoating with appropriate polymers and ceramic materials. The relevanttechnology is known to the expert in this field and is therefore notexplained in greater detail.

For purposes of draining the bile into the hollow micro fibers of thefirst group, these are provided with perforations of the entire wallthickness. The perforations in the hollow micro fibers are made duringmanufacture by means of stretching and laser application. The bilesecretion enters into the hollow micro fibers of the first group via theperforations, said hollow micro fibers constituting the synthetic bilecapillaries, and is passed from there to one of several fluid conductorswhich constitute the synthetic small gall ducts.

In addition to the capillaries and ducts for the bile, the human liverhas vessel branches originating from the hepatic artery (arteriahepatica) and the portal vein (vena portae) which supply the liver lobeswith blood. The surfaces of the hepatocytes are partially enclosed withcell membranes or plasma membranes which function as separation wallsvis-a-vis the neighboring hepatocytes, whereby the distance amounts toapproximately 100 to 200 Å. Between the star-shaped hepatocytesapproaching the central vein (vena centralis) are formed so-called liversinusoids, having a diameter equal to approximately 9 to 12 μm, in whichflows the blood coming from the vessel branches to the central vein.Between the sinusoidal wall, permeable with respect to blood plasma andmacromolecule, and the hepatocytes, there are so-called Disse's spaces.

According to the invention, the branches or capillaries of the humanliver coming from the portal vein and the hepatic artery, are formed bythe hollow micro fibers of the second and third group. These have, inaccordance with the measurements of the real branches, an inner diameterof approximately 1 to 150 μm. According to the properties of thebranches of the portal vein and the hepatic artery, the hollow microfibers of the second and third group have a lower proton conductivityand act as ion- or electrolyte separation membranes.

Ceramic substances and polymers have proven themselves as materialsparticularly appropriate for said purpose. The hollow micro fibers ofthe second and third group respectively issue in a central fluidconductor, the synthetic portal vein or the synthetic hepatic artery.They can be made of bio-compatible material customarily employed forartificial vessels.

On the organ replacement according to the invention, a culture of humanliver cells is grown, preferably in vitro, until the outer surface ofthe hollow micro fibers is fully overgrown with human liver cells. Theliver cells or hepatocytes have in their center the nucleus. Inaddition, the liver cells have the so-called mitochondria, which areequipped with multi-semipermeable membranes with a cut-off accuracy inthe micro-, ultra- or nano-range, with size and load exclusion, or acombination of both, and in which, among others, enzymatic reactionsoccur for the supply of energy.

Finally, the Golgi apparatuses are located in the liver cells insequences, in whose so-called cisterns, lipids can occur.

As soon as sufficient cell growth exists, the organ replacementaccording to the invention can be surgically inserted into the bodyunder application of immuno-therapeutics. It is hereby possible tointroduce the medicaments into the interior of the hollow micro fibers.Needless to say, the artificial liver according to the invention canalso be used as an extracorporeal organ replacement.

Insertion of the organ replacement into the human body is afundamentally possible alternative to the in vitro cell culture growth,so that still healthy liver cells grow incorporeally over the hollowmicro fiber structure. Said method of procedure is specificallyadvisable with only partial liver damage and can, perhaps, be doneendoscopically.

The hollow micro fibers of the organ replacement according to theinvention have an inner diameter of approximately 0.1 to 50 μm. Thiscorresponds to the inner diameter of the natural vessels. In principle,if needed, artificial vessel with different measurements can be used,provided this is logical and technically executable. Hollow micro fibersof said diameter can be produced, for example, via spinning process.Relative to the details of the properties, the possible raw materialsand the manufacturing method, reference is made to the InternationalApplication WO97/26225. As is apparent from this publication, the hollowmicro fibers of the specified dimensions can be produced with highprecision. It is thus possible to keep the variations of diameter andwall thickness of the hollow micro fibers within a range of plus/minus6% as a result of which uniform structure can be guaranteed.

The hollow micro fibers are preferably arranged in a cross-sectionalhoney-comb shaped structure. This corresponds, in turn, to the naturalstructure of the tissue framework around the individual liver lobules.In general, it can be stated that the structure of the hollow microfibers and appropriate fluid conductors should be adapted, to the extentpossible, to the natural structure of the corresponding vessels in orderto obtain maximum compatibility with incorporeal use of theinvention-specific organ replacement. As an alternative to thehoney-comb structure, corrugated cardboard shape arrangement is alsoconceivable or any other structure which results in maximum surface ofcell overgrowth. The size of a honeycomb cell or a corrugated cardboardstructure cell preferably corresponds to approximately the size of ahuman liver lobule.

The bile flows of the liver consist of approximately 97% water, 0.7%bile salt, 0.2% bile pigments, 0.06% cholesterol, 0. 7% inorganic salts,1% fatty acids, lecithin and 0.1% fat. The metabolism of the liver isdetermined by the activity of the human being, by the basic energy needas well as by the food supply. On average, approximately 600 ml bilefluid are generated each day. For that reason, the number and size ofthe perforations is preferably designed in such fashion so that theresulting bile flow amounts to approximately 100 to 3000 ml per day.Naturally, the design may also call for a lower amount of bile fluid,for example if the invention-specific organ replacement is to substituteonly a portion of the human liver. As a rule, a diameter of perforationshave proven adequate which is approximately equal to the diameter of thefilament lumen of the hollow micro fiber, whereby the total area ofperforations should be about 30% if fiber surface.

The hollow micro fibers preferably have a delayed degradation capabilityand are adjustably degradable. As a result, the service life of thehollow micro fibers can be adapted to the age of the person whose liveris to be substituted by the organ replacement according to theinvention.

According to a particularly preferred specific embodiment, the organreplacement according to the invention comprises a porto-caval shunt.This has the benefit of redundancy.

Similarly, the fluid conductors corresponding to the portal vein or thehepatic vein may be designed with a shut-off organ. Construction,manufacture and attachment of such shut-off organs or shunts inartificial vessels are known in the state of the art, for reasons ofwhich the pertinent details are not discussed herein more specifically.

The invention-specific organ replacement can be produced in any selectedsize, in other words a complete liver as well as only a part of same canbe substituted by the organ replacement. The artificial organ accordingto the invention is preferably operated as integral solid foundationreactor with a blood dwelling time of approximately 5 to 250 minutes,whereby occurrence of hemostatis can largely be excluded by theproperties of the hollow micro fibers, in particular based on theirtextile properties. With use of extracorporeal application of theinvention-specific organ replacement, it is possible to select adialysis-corresponding treatment method. In the following, the inventionis described with respect to the attached drawing—but is not limited tosaid embodiment—and its sole figure represents a cross-section through ahollow micro fiber 1 of the first group, constituting a syntheticinterlobular gall capillary. The hollow micro fiber 1 is made of spongymaterial which permits excellent cell growth. In the walls of the hollowmicrofiber 1 are inserted perforations or punchings 2, which serve fordrainage of bile fluid into the lumen of the hollow micro fiber. Thebile flow is beneficially affected by the lipophilic and hydrophilicnature of the outer surface of the hollow micro fibers as well as by thelipophobic and hydrophobic quality of the inner surface of same.

The liver lobules 3 comprising the liver cells are schematicallyindicated on the fiber. The bile fluid which has entered into the hollowmicro fibers 1 through the perforations 2 is further transported to thesmall biliary ducts (not shown in the Fig.) from where is gets into thegall bladder or via the biliary duct directly into the small intestineif the invention-specific organ replacement is located within the humanbody.

An artificial liver is created by the described bile drainage system,with said artificial liver being capable of employment outside as wellas inside the body, since the bile fluid does not decompose the livercells. Thus an organ replacement is provided which is adapted, to theextent possible, to the natural structure and function of the humanliver.

The hollow micro fibers 1 of the first group, which constitute thesynthetic interlobular bile capillaries are interlinked in such fashionwith the hollow micro fibers of the second and third group that astructure is created around each liver lobule replicating the naturalcapillary network. To that end, the hollow micro fibers can be designedeither as tissue or as spun fleece or as tension bond.

It should be noted that in case the term “human liver” is used in thepreceding, this need not be interpreted in the restrictive sense of theword, and that the utilization of the invention-specific organreplacement is not at all limited to humans alone, but can extend aswell to animals with similar liver construction. Needless to say, insuch case potential modifications must be made with respect to sizeand/or structure of the organ replacement according to the invention. Tothat end, the general principle can be established that the organreplacement should be adapted, to the extent possible, to the actualconditions of the to be substituted organ.

What is claimed is:
 1. Bionic organ replacement, presenting a structureof three groups of textile hollow micro fibers, whereby the hollow microfibers of each group issue into a respectively central liquid conductor,wherein the hollow micro fibers (1) of the first group are made ofproton-conducting material and present perforations (2) for the drainageof bile liquid into the interior of the fibers (1) and the one of thesurfaces of essentially each hollow micro fiber (1) of the first groupis hydrophilic and lipophilic, while the other of the surfaces ishydrophobic and lipophobic and, wherein cell cultures can be grown onthe outer surfaces of all of the hollow micro fibers.
 2. Bionic organreplacement, comprising a structure of three groups of textile hollowmicro fibers, whereby the hollow micro fibers of each group issue into arespectively central liquid conductor, whereby cell cultures can begrown of the outer surfaces of all of the hollow micro fibers,characterized in that the hollow micro fibers (1) of the first group aremade of proton-conductive material and present perforations (2) for thedrainage of bile liquid into the interior of the fibers (1) and thesurfaces-of essentially each hollow micro fiber (1) of the first groupare hydrophilic and lipophilic, while the other of the surfaces ishydrophobic and lipophobic.
 3. Bionic organ replacement according toclaim 2, characterized in that the outer surfaces of the hollow microfibers are fully overgrown with human liver cells, cultured in vitro. 4.Bionic organ replacement according to claim 3, characterized in that thehollow micro fibers have an inner diameter of approximately 0.1 to 50μm.
 5. Bionic organ replacement according to claim 3, characterized inthat the hollow micro fibers are arranged, in cross-section, in ahoney-comb shaped structure.
 6. Bionic organ replacement according toclaim 3, characterized in that the liquid conductor is compatible withthe structure of the corresponding human vessel.
 7. Bionic organreplacement according to claim 3, characterized in that the number andsize of the perforations (2) is designed in such manner that a bile flowis possible of approximately 100 to 3000 ml/d.
 8. Bionic organreplacement according to claim 2, characterized in that the hollow microfibers have an inner diameter of approximately 0.1 to 50 μm.
 9. Bionicorgan replacement according to claim 8, characterized in that the hollowmicro fibers are arranged, in cross-section, in a honey-comb shapedstructure.
 10. Bionic organ replacement according to claim 8,characterized in that the liquid conductor is compatible with thestructure of the corresponding human vessel.
 11. Bionic organreplacement according to claim 8, characterized in that the number andsize of the perforations (2) is designed in such manner that a bile flowis possible of approximately 100 to 3000 ml/d.
 12. Bionic organreplacement according to claim 2, characterized in that the hollow microfibers are arranged, in cross-section, in a honey-comb shaped structure.13. Bionic organ replacement according to claim 12, characterized inthat the liquid conductor is compatible with the structure of thecorresponding human vessel.
 14. Bionic organ replacement according toclaim 12, characterized in that the number and size of the perforations(2) is designed in such manner that a bile flow is possible ofapproximately 100 to 3000 ml/d.
 15. Bionic organ replacement accordingto claim 2, characterized in that the liquid conductor is compatiblewith the structure of the corresponding human vessel.
 16. Bionic organreplacement according to claim 15, characterized in that the number andsize of the perforations (2) is designed in such manner that a bile flowis possible of approximately 100 to 3000 ml/d.
 17. Bionic organreplacement according to claim 2, characterized in that the number andsize of the perforations (2) is designed in such manner that a bile flowis possible of approximately 100 to 3000 ml/d.